Is MAPK10 p.Pro459Ser (c.1375C>T) pathogenic?

MAPK10 p.Pro459Ser (c.1375C>T) is classified Uncertain significance in MAPK10 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-16). AlphaMissense: likely benign (0.0729); Very rare (popmax 0.00439%, sas).

How common is MAPK10 p.Pro459Ser (c.1375C>T) in the general population?

MAPK10 p.Pro459Ser (c.1375C>T) is very rare (popmax 0.00439%, sas) (gnomAD).

What do computational predictors say about MAPK10 p.Pro459Ser (c.1375C>T)?

AlphaMissense predicts likely benign (score 0.0729) — an in-silico prediction, not a clinical call.

MAPK10 p.Pro459Ser

c.1375C>T · rs1375872651 · VCV2486418

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0729 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0729	likely benign
REVEL	0.35	indeterminate
SaProt	LLR -4.94	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.9, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 51 kb · p 0.00058 · regional, not allelic
Overall
CADD	25.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00439% South Asian · 4/91,082 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000248% 4/1,614,140 alleles · very rare exomes 4/1,461,822 · genomes 0/152,318 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: MAPK10
Protein: p.Pro459Ser
Coding: c.1375C>T
MANE Select: NM_138982
dbSNP: rs1375872651
Type: single nucleotide variant
Location: chr4:86017248 (GRCh38)
Gene constraint: LOEUF 0.54 · pLI 0.91 (gnomAD)
Structure: AlphaFold pLDDT 80.50 · 65 PDB
Residue 459: the 'disordered' region

Full MAPK10 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAPK10 p.Ala320= Benign ★★ same type
MAPK10 p.Asp351= Benign ★★ same type
MAPK10 p.Val113= Benign/Likely benign ★★ same type
MAPK10 p.Ala353Thr Uncertain significance ★ ⚠ same type
MAPK10 p.Asn89Ser Uncertain significance ★ ⚠ same type
MAPK10 p.Asp141Glu Uncertain significance ★ ⚠ same type
MAPK10 p.Asp267Gly Uncertain significance ★ ⚠ same type
MAPK10 p.Asp315Asn Uncertain significance ★ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/mapk10-p-pro459ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown